The nervous system routinely sends coded signals that result in sensation. Certain types of lesions to either the central or peripheral nervous system can result in an alteration of sensation which leads to pain. Research into persistent or chronic pain has focused mainly on the spinal cord and brain, with little being done to examine the peripheral nervous system. This is so even though researchers and physicians who treat persistent pain syndromes believe that the peripheral nervous system is the origin of much of the pain that needs treatment.
Even though the peripheral nervous system may be considered as the origin of the majority of persistent pain, such pain usually has no known cause. No evidence exists of nerve damage, inflammation or of a biophysical etiology. The lack of knowledge concerning the cause of persistent pain hinders research and development of therapeutics to treat such pain. Many researchers refer to the puzzle of pain when referring to persistent neurogenic pain. The cause of neurogenic pain is only well-defined when there has been a history of direct trauma to a nerve. The majority of persistent neural pain, however, develops slowly near an area of soft tissue injury, without evidence of direct trauma.
Neurogenic pain is pain attributed to a functional disturbance of a nerve or a transitory pertubation, which can occur as a result of alterations and/or injury to nerves. It may occur by a variety of mechanisms including irritation, injury and compression of the peripheral nerves. The symptoms of neurogenic pain may include a burning sensation, tingling, or electric-shock-like feelings that may be triggered by even a very light touch. Human persistent pain conditions are organized into two categories: Complex Regional Pain Syndrome I (CRPS I) and Complex Regional Pain Syndrome II (CRPS II). CRPS I refers to pain without obvious nerve injury, while CRPS II refers to pain with known nerve injury (Merskey and Bogduk, 1994, Classification of Chronic Pain, Second Edition, IASP Press). Current animal models do not represent CRPS I, persistent pain without obvious nerve injury.
Any physical change to a nerve can cause physiologic alterations depending on the nerve's receptor organ and the direction of its electric current. For example, pressure on a nerve is capable of causing nondestructive (non-traumatic) alterations or injury to the nerve that can be seen as changes of characteristics such as in the blood flow of the vasonavorum, in the accumulation of edema within the nerve, in the axonal flow, and in the electrical conductivity and immune cell populations of the nerve. Such changes of pressure on a nerve can result in observable signs and symptoms of nondestructive nerve injury such as behavioral changes of pain with increased sensitivity to light touch and painful sharp touch, licking of paws, edema, and increased sensitivity to heat and cold. Other physical examination signs commonly seen that are associated with more traumatic and/or destructive nerve injury would include sensory numbness and/or hyperalgesia to heat, paw edema, dragging of limb, chewing of paws, tremors, spasms, weakness due to neural loss, and/or paralysis. The functional change in a nerve may depend on the area and force of pressure applied and the resultant changes in extracellular matrix, glial cells, blood flow, lymph circulation, and electrical conductance secondary to the pressure. The consequent alterations in a nerve and their subsequent sensory and behavioral changes may not be immediate, as is seen in a quick high-pressure crush-type injury. In fact, there may be a delay of a few days to several weeks before the onset of neurogenic pain after a tissue injury in humans. Such delayed onset pain conditions can include cervical whiplash, post-traumatic regional persistent pain, post-surgical pain and repetitive trauma syndromes such as radial neuritis. Therefore, animal models of nerve pain must consider the physiological changes occurring in tissue during healing and remodeling after a soft tissue injury, since such changes can result in the delayed onset of persistent neurogenic pain.
Current animal models have focused on production of pain through strategies such as irritating, cutting, crushing, ligating, or freezing the nerves in order to model a human peripheral nerve injury with neuropathic pain. However, such injuries are rarely noted as an initiating etiology in humans. In clinical practice the majority of occupational injuries involving such direct trauma as crush, nerve transection or burns heal without developing chronic neurogenic or neuropathic pain conditions. Examples of animal models using direct neural trauma include: use of chemical irritants injected into a limb or paw (Liu-Chen, et al. 1991, Eur. J. Pharmacol. 15:195-202); transient nerve crush by compressing the nerve with a micro-cuff (Attal, et al. 1994, Pain 59:301-312); freezing the sciatic nerve using the technique of sciatic cryoneurolysis (Willenbring, et al. 1994, Pain 58:135-140; Wagner, et al. 1995, Physiol. Behav. 58:37-41); sciatic nerve partial injury induced by dissecting the nerve lengthwise into two pieces and only ligating one (Seltzer, et al. 1990, Pain 43:205-218); sciatic nerve partial cut where only a part of the nerve is transected (Dougherty, et al. 1992, Brain Res. 20:109-115); sciatic nerve full cut where the nerve is completely transected (Kingery, et al. 1999, Pain 80:555-566); nerve root ligatures where the lumbar nerve roots are ligated (Kim, and Chung, 1992, Pain 50:355-363; Choi, et al. 1994, Pain 59:369-376); polyethylene cuffs to produce a compression injury (Mosconi and Kruger, 1996, Pain 64:37-57); use of hemostatic oxidized cellulose that on one side was saturated with an inflammatory stimulus, carrageenan, or complete Freund's adjuvant (Eliav, et al. 1999, Pain 83:169-182); bee venom injected into rat paw (Chen, et al. 2000, Neurosci. Lett. 284:45-48); scalding of rat paw (Lofgren, et al. 1997, Acta Physiol. Scand. 161:289-294); photochemically-induced laser lesion of sciatic nerve (Gazelius, et al. 1996, Neuroreport. 4:2619-2623); use of zymosan on the sciatic nerve (Chacur, et al. 2000, American Pain Society Poster Presentation); and a spared nerve injury model where two or three terminal branches of the sciatic nerve are transected (Decosterd and Woolf, 2000, Pain 87:149-158). All of these animal models rely on production of a destructive nerve injury through direct nerve trauma, irritation, or an acute immune response. A model extensively studied for chronic pain is the Chronic Constriction Injury (CCI) model where a sciatic nerve injury is induced by tying four chromic gut sutures loosely around the nerve (Bennett and Xie, 1998, Pain 33:87-107). However, this model produces animals that have difficulty walking due to the immediate, acute pain and swelling seen in the leg on which the procedure is performed. As a result, special attention to animal care is needed for these animals for 3 to 4 days. None of the current models create persistent neurogenic pain in animals that are fully ambulatory within minutes of the procedure and require no special care.
In addition, current animal models of neuropathic pain result in sudden acute inflammatory pain and do not mimic the prolonged normal tissue repair physiology which occurs after many human injuries. Perineural tissue changes can occur after an injury that leads to altered functioning of a nerve and to the ultimate development of pain-related behaviors. In this regards, none of the current models represent the gradual onset of neurogenic pain, since the neuropathic pain they represent is initiated with a very direct injurious method.
Furthermore, all current animal models involve some type of known nerve injury. Yet, the majority of persistent “nonmalignant” pain treated by physicians has no known nerve injury as a cause, although the origin is attributed to being neurogenic or neuropathic. Persistent pain can develop as a response to often clinically, non-detectable tissue injury, not only as a response to direct trauma. After a soft tissue injury, there appears to be a functional disturbance of an associated nerve, which can lead to the demonstration of pain behavior. The cause or location of this disturbance, perturbation or ectopic firing on a nerve is not currently identified.
There is a long-standing need for an animal model representing patients with chronic pain without nerve damage. The need for an animal model for pain without clinical evidence of nerve injury has been recognized and preliminary attempts have been made. Reyna et al. (ICLAS, Palma de Malloren, May 26-28, page 226, 1999) developed an open surgical rat model for CRPS I that involved surgical placement by the tibial nerve of collagen. This surgical model produced pain responses characteristic of known neurogenic pain in the rats. For example, the responses were delayed in onset by about 14 days. The responses included sensitivity to light touch (mechanical allodynia), and persisted for up to 43 days. In addition, these animals exhibited an analgesic response to morphine sulfate and gabapentin. However, the creation of this animal model involved a surgical procedure to expose the posterior tibial nerve on one leg of the animal. The open surgical procedure could cause a certain degree of direct tissue injury. Thus, additional models for persistent neuropathic pain are needed, in particular, models that involve minimal tissue injury.